Topical therapies are an appropriate alternative to systemic therapies for treatment of cutaneous leishmaniasis since they are associated with lower costs, fewer side effects, and the possibility of self- administration. It is hypothesized tht a combination of novel fabrication technologies (e.g., multiple foci two photon polymerization of a zirconium oxide hybrid material, polydimethylsiloxane micromolding, and piezoelectric inkjet printing) and conventional drug delivery materials (e.g., a biodegradable acid anhydride copolymer containing alternating maleic anhydride and methyl vinyl ether groups and the pharmacologic agent amphotericin B) can be used to prepare amphotericin B-loaded biodegradable polymer microneedles for topical therapy of cutaneous leishmaniasis at lower amphotericin B doses than conventional methods. Methodology: Objective I will involve chemical, physical, mechanical, and in vitro biological characterization of amphotericin B-loaded biodegradable polymer materials, microneedles, and microneedle arrays. Objective II will involve characterization of amphotericin B-loaded microneedles and microneedle arrays with porcine skin. Objective III will involve an in initial toxicology study to determine an appropriate dose level for microneedle- based amphotericin B delivery. Efficacy experiments against an Old World cutaneous leishmaniasis species (L. major) and a New World cutaneous leishmaniasis species (L. mexicana) will be undertaken; comparisons to conventional agents (e.g., intravenously-delivered amphotericin B liposomes, topical paromomycin, and oral miltefosine) will be made. Alterations in kidney function in animal subjects that receive amphotericin B-loaded microneedles will be assessed from serum blood urea nitrogen, creatinine, albumin, and total protein values. Innovation: The stratum corneum layer of the skin obstructs transport of many types of pharmacologic agents, including charged, large, and/or polar pharmacologic agents. It is hypothesized that microneedle-based topical treatment of amphotericin B may be achieved at lower amphotericin B doses than conventional amphotericin B delivery methods since microneedles physically disrupt the stratum corneum layer. Processing amphotericin B- loaded microneedles is also complicated by the fact that amphotericin B exhibits poor solubility in aqueous solutions. Although incorporation of amphotericin B within microneedles may be difficult via conventional methods (e.g., mixing or dip coating), piezoelectric inkjet printing may be used to deposit an amphotericin B coating onto the surfaces of microneedles. The input and processing costs for amphotericin B-loaded microneedles ($ 0.10/device) are quite low and are significantly lower than those for liposomal formulations. Significance: The data from the proposed program will facilitate studies comprehensive in vivo studies and eventually clinical studies that will examine the effectiveness of amphotericin B-loaded microneedles.